Nuclear Factor-κB Accounts for the Repressor Effects of High Stromal Cell–Derived Factor-1α Levels on Tac1 Expression in Nontumorigenic Breast Cells

Abstract

Stromal cell -derived factor-1A (SDF-1A) is a CXC chemokine that interacts with CXCR4 receptor. Tac1 encodes peptides belonging to the tachykinins, including substance P. SDF-1A production is decreased in Tac1 knockdown breast cancer cells and is also reduced in these cancer cells following contact with bone marrow stroma when Tac1 expression is increased. Here, we report on the effects of relatively high and low SDF-1A levels on Tac1 expression in nontumorigenic breast cells MCF12A. Reporter gene assays, Northern analyses, and ELISA for substance P showed increased Tac1 expression at 20 and 50 ng/mL SDF-1A and reduced expression at 100 ng/mL. Omission of the untranslated region showed a dose-dependent effect of SDF-1A on reporter gene activity, suggesting that receptor desensitization cannot account for the suppressive effects at 100 ng/mL SDF-1A. Tac1 expression at high SDF-1A involves an intracellular signaling pathway that incorporates the activation of phosphatidylinositol 3-kinase-phosphoinositidedependent kinase-1-AKT-nuclear factor-KB (NF-KB). The major repressive effect occurs via NF-KB located within exon 1. In summary, NF-KB is involved in the repression of Tac1 at higher levels of SDF-1A in MCF12A. These results are relevant to dysfunction of Tac1 in breast cancer cells and also provide insights on the behavior of breast cancer cells as they traverse across gradient changes of SDF-1A. (Mol Cancer Res 2007;5(4):373 -81)

Extracellular Signal-Regulated Kinase 1/2 and c-Jun NH2-Terminal Kinase, through Nuclear Factor-κB and Activator Protein-1, Contribute to Caerulein-Induced Expression of Substance P and Neurokinin-1 Receptors in Pancreatic Acinar Cells

“…The increased transcription of PPT-A probably contributed to the increased expression of SP. These observations were in agreement with the results for other models, which also highlighted the involvement of NF-B activation in the increased expression of PPT-A and NK1R (Guo et al, 2004;Reed et al, 2005;Corcoran and Rameshwar, 2007).…”

Evidence for regulatory diversity and auto-regulation at the TAC1 locus in sensory neurones

“…Thus, by deduction, LPS is more likely to modulate TAC1prom activity through NFκβ than MAPkinase pathways [21]. In keeping with this hypothesis there have been previous reports of highly conserved NFκβ binding in TAC1 exon 1 [48] and we have used bioinformatics to detect the presence of NFκβ binding sites close to the human TAC1 transcriptional start site (data not shown).…”

Tumor microenvironment and breast cancer progression

“…miR-9-1 in breast cancer). 78 In relation to this finding and observations that the distant tumor microenvironment can affect metastasis, it was recently reported 79 that miRNAs against Tac-1 mRNA may affect quiescence of breast cancer cells in the marrow cavity, promoting bone marrow metastasis.…”